Effect of memantine pharmacology. (A) Effect of memantine pharmacology as represented by a 0.5% decrease in N-Methyl-D-aspartic acid (NMDA) conductance on excitatory-excitatory and 1% decrease of NMDA conductance on excitatory-inhibitory glutamate synapse on cortical AD network outcome. Memantine leads to a deterioration in the very early stage MCI (mild cognitive impairment) that further turns into a stronger positive effect as the pathology (i.e. loss of synapses and neurons) advances. (B) Sensitivity analysis of the difference between memantine and placebo effect for different values of amount of synapse and neuronal cell loss. The MCI state is defined as 3% synapse loss and 4% neuronal cell loss (indicated by ★ on the figure). A negative outcome corresponds to a decrease in performance after memantine. The effect of memantine is conserved over a range of synapse loss (1-5%) and neuronal cell loss (4-5%).